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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

US-approved intra-articular hyaluronic acid injections are safe and effective in patients with knee osteoarthritis: systematic review and meta-analysis of randomized, saline-controlled trials

LE Miller and JE Block.

Review published: 2013.

Link to full article: [PMC free article: PMC3767581]

CRD summary

This review concludes that intra-articular hyaluronic acid injections for symptomatic knee osteoarthritis were safe and effective. The former conclusion may have confused the absence of evidence with the evidence of absence; the latter conclusion did not sufficiently consider variability in effectiveness or potential biases in the evidence-base. Thus, these conclusions cannot be considered reliable.

Authors' objectives

To determine the safety and efficacy of intra-articular hyaluronic acid injections for symptomatic knee osteoarthritis.

Searching

MEDLINE and EMBASE were searched using specified search terms up to June 2013. Reference lists of included studies and relevant meta-analyses were searched manually. Only full-text publications in English were assessed for inclusion.

Study selection

Eligible for inclusion were randomised, saline-control studies that used an injection of a US-approved hyaluronic acid product in patients with a primary diagnosis of knee osteoarthritis. Eligible studies were required to have identical treatment and follow-up conditions between intra-articular hyaluronic acid and saline-control groups, and at least one extractable efficacy or safety outcome. Studies were excluded if concomitant interventional therapies were uniformly administered.

In included trials, the main efficacy outcomes were knee pain and function. Safety outcomes included serious adverse events, treatment-related serious adverse events, subject withdrawals for any reason, and adverse event-related subject withdrawals occurring at any time during follow-up. The most commonly studied viscosupplements were Hyalgan, Synvisc, Supartz/Artzal, Orthovisc, Gel-One, and Euflexxa. The total number of injections received by patients ranged from one to five. Baseline characteristics of patients were similar in treatment and control groups (details reported).

The number of reviewers determining eligibility was not stated.

Assessment of study quality

Study quality was assessed using the Jadad scale.

The number of reviewers assessing quality was not stated.

Data extraction

Sample sizes, mean values and standard deviations were extracted pre- and post-intervention for treatment and control groups, to derive standardised mean differences. Time of follow-up was variable and stratified into two time periods: four to 13 weeks; and 14 to 26 weeks. Efficacy data reported outside of these time frames were excluded. Where a choice of values were available, final values were used. When a single control group served multiple treatment groups within a study, the sample size of the control group entered into the meta-analysis was adjusted based on the number of treatment groups. Adverse events were extracted (where reported) and expressed as risk differences.

Data were extracted from eligible peer-reviewed articles by one author and were verified by a second author.

Methods of synthesis

Random-effects meta-analysis was used to calculate two separate effect size statistics for each efficacy outcome: pre-treatment to post-treatment standardized mean difference for intra-articular hyaluronic acid; and standardized mean difference for intra-articular hyaluronic acid versus saline control. Heterogeneity was quantified using Ι² with values of 25% or lower representing low inconsistency, 50% representing moderate inconsistency, and 75% or higher representing high inconsistency.

Publication bias was assessed using funnel plots and Egger’s test

Results of the review

Twenty-nine trials (4,866 patients: 2,673 in the intra-articular hyaluronic acid group; 2,193 in the saline group) were included in the review. Trial quality was assessed as moderate with a median Jadad score of 3.

Comparisons with pre-treatment values showed statistically significant improvements in knee pain (SMD 1.14 for 14 to 26 weeks follow-up; SMD 1.37 for four to 13 weeks follow-up) and function (SMD 1.07 for 14 to 26 weeks follow-up; SMD 1.16 for four to 13 weeks follow-up) following the use of intra-articular hyaluronic acid injections (95% confidence intervals all reported in the review).

Compared to saline controls, statistically significant greater improvements in knee pain (SMD 0.38 for 14 to 26 weeks follow-up; SMD 0.43 for four to 13 weeks follow-up) and knee function (SMD 0.32 for 14 to 26 weeks follow-up; SMD 0.34 for four to 13 weeks follow-up) were shown with the use of intra-articular hyaluronic acid injections, although the sizes of these effects were small and the corresponding 95% confidence intervals were wide.

Heterogeneity was substantial to moderate for all efficacy outcomes, some of which illustrated small study effects consistent with publication bias (details reported).

There were no statistically significant differences between intra-articular hyaluronic acid and saline controls for any reported safety outcomes.

Authors' conclusions

The authors concluded that intra-articular injection of US-approved hyaluronic acid products was safe and efficacious in patients with symptomatic knee osteoarthritis.

CRD commentary

The reviewers addressed a clear question and used appropriate methods to obtain information, although checking trial registries would have usefully augmented attempts to avoid publication bias. Duplicating all stages of the review process would have increased repeatability.

Trial quality was assessed as moderate, but details of the potential biases were not reported. The degree to which possible biases, such as lack of intention-to-treat analyses and limitations in blinding, impacted on the results was unclear. Similarly, there was substantial heterogeneity surrounding efficacy outcomes. The extent to which this heterogeneity resulted in inconsistency was unreported but the potential for confounding was high. This may have been especially important for factors such as the inclusion of different molecular weights of hyaluronic acid and different injection schedules (which ranged from once weekly to a series of five injections). The limited duration of and size of randomised trials mean that safety outcomes were imprecisely estimated, so the authors' conclusions on safety risk may have confused lack of effect with lack of ability to detect effects. Thus, although the authors' conclusions do reflect the evidence presented, they cannot be considered reliable.

Implications of the review for practice and research

The authors did not state any implications for future practice or research.

Funding

HA Viscosupplement Coalition (Bioventus LLC, Durham, NC; DePuy Synthes Mitek Sports Medicine, Raynham, MA; Ferring Pharmaceuticals Inc., Parsippany, NJ; Fidia Pharma USA, Inc., Parsippany, NJ; Zimmer, Inc., Warsaw, IN), USA

Bibliographic details

Miller LE, Block JE. US-approved intra-articular hyaluronic acid injections are safe and effective in patients with knee osteoarthritis: systematic review and meta-analysis of randomized, saline-controlled trials. Clinical Medicine Insights: Arthritis and Musculoskeletal Disorders 2013; 6: 57-63. [PMC free article: PMC3767581] [PubMed: 24027421]

Indexing Status

Subject indexing assigned by CRD

MeSH

Anti-Inflammatory Agents, Non-Steroidal; Hyaluronic Acid; Humans; Osteoarthritis, Knee; Injections, Intra-Arterial

AccessionNumber

12013053365

Database entry date

15/10/2013

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 24027421

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